Diallyl Trisulfide Suppresses Angiotensin II-Induced Vascular Remodeling Via Inhibition of Mitochondrial Fission
Diallyl Trisulfide Suppresses Angiotensin II-Induced Vascular Remodeling Via Inhibition of Mitochondrial Fission
复制标题
二烯丙基三硫化物通过抑制线粒体裂变抑制血管紧张素 II 诱导的血管重塑
DOI：
10.1007/s10557-020-07000-1
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发表时间：
2020-06-20
影响因子：
3.4
通讯作者：
Li, Bao
中科院分区：
文献类型：
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作者：
Lu, Zhao-Yang;Qi, Jia;Li, Bao
目的在高血糖诱导的内皮细胞凋亡和糖尿病小鼠模型中，我们已经证明二烯丙基三硫化物(DATS)可以改善线粒体分裂和氧化应激。本研究的目的是研究DATS是否减轻Ang II诱导的血管平滑肌细胞(VSMC)表型转换和血管重塑，如果是的话，确定潜在的分子事件。方法雄性C57BL/6小鼠皮下注射血管紧张素Ⅱ2周，建立血管重塑模型。给动物腹腔注射DATS或赋形剂。对生理参数、血管形态和分子标记进行评估。在体外实验中，用DATS或不加DATS处理VSMCs 1h，然后用Ang II刺激VSMC，并观察其线粒体形态和表型转换。结果在原代培养的小鼠VSMC中，我们发现依赖于Drp1的线粒体分裂调节线粒体活性氧物种(MtROS)的产生，最终促进Ang II诱导的VSMC的增殖、迁移和表型转换。此外，Ang II被发现上调Rho相关的螺旋线圈蛋白激酶1(ROCK1)，该蛋白通过磷酸化Drp1来调节线粒体分裂和VSMC表型转换。然而，血管紧张素转换酶II的生物学效应被DATS取消。我们发现，在血管紧张素转换酶II诱导的血管重塑的动物模型中，DATS显著减轻线粒体分裂、VSMC分化和血管壁增厚，这与在VSMC中的作用一致，这是由ROCK1/Drp1信号调节的。结论DATS通过以ROCK1依赖的方式抑制Drp1介导的线粒体分裂，从而减轻Ang II诱导的血管重构。
Objective We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. Methods Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. Results In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. Conclusions Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.